Herpes simplex virus (HSV) causes diseases in humans which range in severity from the benign cold sore to life-threatening encephalitis. Herpes simplex virus (HSV) resides in a latent state in neurons of sensory and sympathetic ganglia. During latency, infectious virus is not detectable; however, the latent virus can reactivate to produce recurrent lesions and transmissible virus. The mechanisms involved in the establishment, maintenance and reactivation of latent HSV are not understood.
It is known that nerve growth factor (NGF) endogenous to the central nervous system (CNS) and peripheral nervous system (PNS) provides trophic support critical to mature sensory neuronal survival [E. M. Johnson, Jr. et al., Nature (London), 314, 751-752 (1985)]. Nerve growth factor is synthesized and released by peripheral target tissue. NGF binds specifically to receptors on the nerve terminals and is retrogradely transported to the neuronal soma [I. A. Hendry et al., Brain Res., 68, 103-121 (1974)]. Sympathetic and neural crest-derived sensory neurons in vivo and in vitro require NGF for maintaining normal function and, depending on age and cell type, for survival [H. Thoenen et al., Physiol. Rev. 60, 1284-1335 (1980)].
The HSV genome resides within neuronal cells during latency. Reactivation of latent HSV has been attributed to a number of diverse causes. For example, the loss of trophic support provided to the neuron by the peripheral target has been suggested to result in reactivation of latent HSV [R. W. Price et al., Infect. Immun., 19, 523-532 (1978)]. Examples of other reactivating stimuli are UV irradiation and fever [W. A. Blyth et al., J. Gen. Virol., 33, 547-550 (1976); and S. L. Warren et al., J. Exp. Med., 71, 155-168 (1940)]. Still other reactivating stimuli may act by reducing or interrupting retrogradely transported neurotrophic support from neuronal targets, such as by central rhizotomy or axotomy [C. A. Carton et al., N. Engl. J. Med. 246, 172-176 (1952); M. A. Walz et al., Science, 184, 1185-1187 (1974)].
Others have investigated HSV latency, reactivation and replication. For example, cells of neural crest origin (PC-12, pheochromocytoma cell line) cultured in the presence of NGF can be infected with herpes simplex virus and produce progeny virus [L. I. Pizer et al., Acta. Neuropathol. (Berl.), 44, 9-14 (1978)]. Establishment and maintenance of latency of HSV-infected neuronal cells have been accomplished using complicated combinations of chemical agents, physical conditions and biological reagents. For example, one HSV latency model requires (i) BVDU and IFN-.alpha. to establish latency, (ii) elevated temperature to maintain latency, and (iii) temperature reduction along with human cytomegalovirus super-infection to reactivate the virus [B. L. Wigdahl et al., Virology, 127, 159-167 (1983)].
Aside from those attempts to establish models to investigate the in vivo interactions of HSV with neuronal cells, present therapeutic approaches to treatment of animals infected with active HSV usually depend upon the administration of drugs as anti-viral agents. Many of these anti-viral agents are minimally effective, however, or must be utilized at sub-optimal concentrations because of severe side effects of the anti-viral agent on the animal. Hence, a need exists for an agent which can ameliorate viral disease while having little detrimental effect on host tissues.